Continuing Education Activity

Transplant rejection can be classified as hyperacute, acute, or chronic. Hyperacute rejection is usually caused by specific antibodies against the graft and occurs within minutes or hours after grafting. Acute rejection occurs days or weeks after transplantation and can be caused by specific lymphocytes in the recipient that recognize human leukocyte antigens in the tissue or organ grafted. Finally, chronic rejection usually occurs months or years after organ or tissue transplantation. Various mechanisms involving chronic inflammation, humoral, and cellular immune reactions play essential roles in the immunopathogenesis of chronic rejections. This activity reviews the evaluation and management of chronic transplant rejections and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Objectives:

• Identify the pathophysiology of chronic transplant rejection.
• Describe the typical presentation of a patient with chronic transplant rejection.
• Explain how to manage chronic transplant rejection.
• Explain the importance of improving coordination among the interprofessional team to enhance care for patients affected by chronic transplant rejection.

Introduction

Transplant rejection can be classified as hyperacute, acute, or chronic. Hyperacute rejection is usually caused by specific antibodies against the graft and occurs within minutes or hours after grafting. Acute rejection occurs days or weeks after transplantation and can be caused by specific lymphocytes in the recipient that recognize HLA antigens in the tissue or organ grafted. Finally, chronic rejection usually occurs months or years after organ or tissue transplantation. Various mechanisms involving chronic inflammation, humoral, and cellular immune reactions play an essential role in the immunopathogenesis of chronic rejection.

Etiology

The etiology of chronic rejection is incompletely understood. Glinton et al. reported that a vital determinant of the complication of chronic solid organ allografts is by a vascular disease component of the transplanted graft. Their review, however, focused on cardiac transplantation only. In cardiac allograft vasculopathy, histologic evidence suggests that the accumulation and activation of phagocytes can be a contributing factor. Phagocytic cells such as macrophages, monocytes, and immature dendritic cell subsets are found in this type of chronic cardiac transplant rejection. Furthermore, myeloid phagocytes crosstalk with B and T lymphocytes while also signaling and activating vascular smooth muscle cells and fibroblasts, and these can cause fibrous intimal thickening.[1] Chronic renal allograft rejection has been labeled as interstitial fibrosis and tubular atrophy to help reflect the underlying histology and etiology. Chronic rejection is now cited as the leading cause of graft rejection.

Epidemiology

The overall incidence and prevalence of chronic allograft nephropathy (CAN) in biopsies of renal allograft tissues depends on the timing and the indication of such graft biopsies. In protocol biopsies, in the first year post-transplantation, it has been reported that the prevalence can be as high as 94% (grade I) and up to 100% after ten years. 

In the United States, mortality in patients on chronic hemodialysis is significantly higher in winter months than in the summer. It is unknown whether a seasonal difference exists, however, for mortality or graft failure among kidney transplant recipients. One report showed that there was a significant annual variation of deaths due to graft failures. [2]

Pathophysiology

Chronic allograft rejection can be caused by antibody-dependent complement activation lesions as well as cell arteritis leading to the development of interstitial fibrosis/tubular atrophy (IF/TA).[3] This injury can appear early after transplantation. At 1-year post-transplant, greater than 81% of the kidneys have minimal lesions of IF/TA that tend to progress over time; these lesions affect greater than 50% of transplanted kidneys with severe lesions at five years.

The 2011 Banff meeting focused on diagnostic criteria for late-antibody mediated rejection.  In this review, there was the recognition of CD4-negative antibody-mediated rejection, in which endothelial activation and NK cells were suggested as the primary causes of chronic reaction.[4] Other proposed pathophysiologic mechanisms include:

• Calcineurin inhibitors (CNI) toxicity
• Chronic dysfunction of the solid organ causing premature graft loss
• Alloimmunization to minor HLA antigens
• Production of interferon-gamma and IL-2 by Th1 lymphocytes
• Secretion of cytokines by endothelial cells

Histopathology

The main histological finding in biopsies of rejected organs is arteriosclerosis that causes a progressive luminal narrowing of graft vessels. This is typically referred to as a vasculopathy or graft vascular disease. This entity is often accompanied by graft tissue (parenchymal) fibrosis.[5] For example, livers with chronic rejection show a decreased number of bile ducts on biopsy and obliteration of small arteries. Correspondingly, lung rejection is characterized by bronchiolitis obliterans.  The presence of endothelial injury and subsequent inflammation has been suggested as the inciting cause of this vascular dysfunction.

History and Physical

Individuals presenting with chronic transplant rejection will have had a previous history of organ or tissue transplantation (for example, kidney, liver, and lung) for any of many chronic medical conditions. The symptoms and signs of rejection depend on the organ transplanted; for instance, a chronic kidney rejection causes fatigue, fever, flu-like symptoms, anuria or decreased urine output, generalized edema, and pain or tenderness at the site of transplantation. Other signs and symptoms of organ rejection can include:

• Jaundice
• Dark urine
• Itching
• Nausea and vomiting
• Abdominal swelling or tenderness
• Cough, shortness of breath
• Recurrent infections
• Arterial hypertension
• Proteinuria
• Fatigue
• Weight gain 
• Premature death
• Anorexia
• Anemia
• Opportunistic neoplasia
• Pulmonary edema
• Atherosclerosis

Evaluation

Various laboratory tests can be ordered to test for chronic rejection. These may include the following:

• Twenty-four-hour urine collection
• Blood chemistry
• Complete blood cell count
• Electrocardiogram
• Chest x-ray
• CT (computed tomography) of the abdomen
• Abdominal ultrasonography
• Histological studies
• HLA typing (This will test for histocompatibility between donor and recipient. The most critical loci are HLA-A, HLA-B, and HLA-DR.)
• Serology (testing for HIV; hepatitis B and C)

In renal transplantation, urinary samples can prove useful to determine rejection.  Tubular epithelial cells, casts, oxalate crystals (sand-glass shaped), dirty background, increasing erythrocyturia, mixed cell clusters, lymphocytes, and mitoses all may be observed.

"Owl-eye" cells milk-glass nuclei, sometimes with eosinophilic condensation, typically characterize cytologic examination of the voided urine in CMV infection.[6] Serological tests can further help in differentiating CMV-infection from allograft rejection.

Treatment / Management

The treatment of organ rejection depends on the type of injury and underlying etiology. In chronic kidney rejection, complications including arterial hypertension, pulmonary edema, and uremia should be managed through various therapeutic options, including but not limited to hemodialysis, hemofiltration, and the use of diuretics.

As a general statement, most infectious causes should be treated with specific, directed antimicrobials.

In diabetic nephropathy, the albumin to creatinine ratio can be used to guide therapy.  If this ratio is greater than 3, inhibition of the renin-angiotensin system is recommended with an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB). This therapy should be pursued even in the setting of normal blood pressure to help protect the donor's kidney.

Tight glucose control is recommended in the setting of hyperglycemia.  In type 1 diabetes mellitus, therapy is typically accomplished with insulin, and in non-insulin-dependent diabetes mellitus, therapy is usually with a biguanide or sulfonylurea.

In end-stage rejection, there may be a consideration for retransplantation of the organ or tissues.

Differential Diagnosis

The differential diagnosis for chronic rejection is broad but includes acute rejection, infection (CMV), medication toxicity (immunosuppressants), posttransplant lymphoproliferative disease, or technical problems with vascular or structural anastomotic complications.

Pertinent Studies and Ongoing Trials

The FTY720 (fingolimod) is a novel immunosuppressive agent that has been investigated in the last few decades. FTY is highly effective in prolonging graft survival in preclinical models of transplantation and multiple sclerosis. FTY720 is an immunomodulator. Its mode of action differs completely from traditional immunosuppressants. It is a new class of drugs named sphingosine 1-phosphate receptor (S1P-R) modulators.[7][8] In laboratory animals, S1P receptor activation with fingolimod activates anti-inflammatory and anti-apoptotic pathways, leading to improved myocardial salvage by reducing cardiac fibrosis.[9]

ASP0028, an S1P1/S1P5-selective agonist, with comparable efficacy to FTY720 and wider safety margins than FTY720, showed the efficacy and safety when it was co-administered with suboptimal-dose of tacrolimus in a monkey renal transplantation model. ASP0028 administration remarkably reduced peripheral lymphocytes, including subsets of CD4+/ or CD8+/naive and memory cells, CD4+/Treg cells, and B cells, but not CD4+/ or CD8+/effector memory cells and natural killer (NK) cells. These data support the finding that ASP0028 and tacrolimus prolong renal allograft survival in primates.[7]

Staging

The Banff grading system is a classification of the severity of chronic renal allograft nephropathy. This was originally implemented in 1997 and updated subsequently in 2005, 2007, 2009, 2013, and 2017.[3][4] This schema grades disease severity, according to interstitial fibrosis, atrophy, and loss of tubules (IF/TA):

• Grade I: Mild fibrosis of the interstitium and mild atrophy of the tubules, either with or without specific glomerular or vascular findings that can suggest chronic allograft nephropathy.
• Grade II: Moderate interstitial fibrosis (affecting 25% to 50% of the cortical area) and moderate tubular atrophy (involving 26% to 50% of the area of the cortical tubules). 
• Grade III: Severe interstitial fibrosis (affecting greater than 50 percent of the cortical area) and tubular atrophy (involving greater than 50% of the area of the cortical tubules).

Prognosis

As many as one-third of cadaveric kidney transplant recipients suffer graft loss within five years of transplantation.

Unfortunately, changes in immunotherapy have proven to be mostly ineffective in changing the prognosis for patients with established chronic allograft nephropathy.

Prevention, early diagnosis, management of both comorbidity, and complications of chronic kidney disease can improve the survival of patients with transplant failure.

Complications

The success of organ transplantation depends on the use of immunosuppressive drugs to control the alloimmune response. The most frequent drugs used for kidney transplantation include a cocktail of 3 medications, including a drug that inhibits T-cell activation (cyclosporin, tacrolimus, or sirolimus), an antiproliferative (6-mercaptopurine, or mycophenolic acid), and an anti-inflammatory agent (corticosteroids). 

Chronic organ rejection can be associated with a high mortality rate and may result in various complications, including kidney failure, liver failure, chronic pulmonary disease, pancreatic insufficiency, arteriosclerosis, and blood dyscrasias.

Other complications include CMV infection and infectious diseases caused by bacterial, viral, fungal, protozoal, or mixed. Excessive immunosuppression can cause the emergence of BK polyomavirus resulting in BK nephropathy and may account for one to ten percent of allograft failure.

A late complication of renal transplantation is the recurrence of the original disease (diabetic nephropathy).

The development of malignancy is a late complication of chronic organ rejection. For example, the incidence of lymphoma is approximately 40 times greater in transplant recipients than in the general population. Other tumors that may be observed include skin cancer, Kaposi sarcoma, and lymphoma due to Epstein-Barr virus activation.

Deterrence and Patient Education

Patients must be compliant with immunosuppressive drugs to avoid organ rejection and improve their quality of life. Similarly, patients must also comply with the treatment of any underlying comorbidities.

Pearls and Other Issues

• The use of immunosuppressants in chronic rejection does not adequately prevent it. High dosages may be used without an observable therapeutic response. This suggests that chronic rejection may involve many other mechanisms rather than only immunological pathways. Until the pathophysiology and immunopathogenesis of this rejection are fully understood, it is difficult to create novel therapeutic interventions to tackle this problem.
• The better the HLA matching between donor and recipient, the more successful the organ transplant will be and over a longer period.

Enhancing Healthcare Team Outcomes

An interprofessional team educates and manages the patient with chronic rejection. The team consists of primary care, medical and surgical specialists, specialty trained nurses, and pharmacists. Since this condition is life-threatening, the health care providers should advise the patient fully about all other treatment options, psychological support, and in extreme circumstances, consideration for an organ or tissue re-transplantation. Nephrology, cardiology, and transplant nurses provide education to patients and their families, monitor patient status, and direct feedback to the team. Pharmacists evaluate prescribed medications, check for drug-drug interactions, and participate in patient education. In this way, the team can improve outcomes. [Level 5]